As liver regeneration therapy at present, glucagon-insulin therapy has been clinically used for fulminant hepatitis. However, effectiveness thereof is not satisfactory. Further, among hepatoma patients, hepatoma resection is not applied to those with complication of chronic hepatitis or cirrhosis showing decrease of hepatic residual function, because sufficient liver regeneration cannot be expected after the resection and a problem of hepatic failure may arise. Under the background circumstances, it is strongly desired to develop a medicament having a promoting action on liver regeneration which is safely usable for prophylactic and/or therapeutic treatment of fulminant hepatitis or hepatic failure after hepatoma resection. As agents for promoting liver regeneration in a level of fundamental experiment, growth factors such as hepatocyte growth factor, transforming growth factor-α and epidermal growth factor, amino acids such as valine, leucine, alanine and glutamine, thrombocyte, thrombopoietin, anti-kallikrein antibodies, and the like have been reported (Non-patent documents 1 to 5, Patent documents 1 to 5).
In particular, hepatoma is a disease associated with poor prognosis, and it is known that the disease recurs at a high rate even after treatment. For example, it is impossible to use a substance as a medicament that induces transformation of hepatocytes or a substance having proliferation promoting action on cancer cells, even if said substance has promoting action on hepatocyte proliferation, because the substance may promote recurrence of hepatoma. Therefore, in order to improve treatment results of hepatoma and prevent recurrence thereof over a long period of time, it is an important subject to develop a medicament that suppresses oncogenesis in the liver and promotes liver regeneration.
As substances that suppress oncogenesis in the liver, retinoids such as all-trans-retinoic acid (ATRA), 9-cis-retinoic acid (9CRA), and fenretinide are reported, and among them, ATRA is reported to induce the proliferation of mouse hepatocytes. However, ATRA is also reported to promote oncogenesis in a mouse liver carcinogenic model, and therefore safety of ATRA is questioned. Further, it is also known that administration of ATRA induces serious side reactions such as retinoic acid syndrome (various symptoms including pyrexia, dyspnoea, retention of pleural effusion, lung infiltration, interstitial pneumonia, pulmonary congestion, hypoxemia, hypotension, hepatic failure, renal failure, and multiple organ failure), and leukocytosis. Therefore, at present, any safe substance that suppresses liver oncogenesis and promotes proliferation of hepatocytes has not yet been known.
One of polyprenyl compounds, (2E,4E,6E,10E)-3,7,11,15-tetramethyl-2,4,6,10,14-hexadecapentaenoic acid (hereinafter in the specification, this substance may also be referred to as “NIK-333”) is known to have affinity to retinoic acid-binding proteins and retinoic acid receptors, and have differentiation inducing action and apoptosis inducing action for hepatoma cells. Recurrence of hepatoma after radical cure was significantly suppressed by long-term administration of NIK-333 over one year, and thus hepatoma recurrence suppressing action of NIK-333 has been confirmed (Non-patent document 6). However, it has been absolutely not known so far that polyprenyl compounds promote proliferation of hepatocytes. In addition, it has been reported that NIK-333 does not affect proliferation of primarily cultured mouse hepatocytes at a concentration inducing apoptosis of hepatoma cells (Non-patent documents 7 and 8), and it has also been reported that NIK-333 delays DNA synthesis of a regenerated liver in a rat partially hepatectomized model (Non-patent document 9).    Non-patent document 1: Biohem. Biophys. Res. Commun., 133, pp. 1042-1050, 1985    Non-patent document 2: Proc. Natl. Acad. Sci. USA, 86, pp. 1558-1562, 1989    Non-patent document 3: Cell, 18, pp. 153-163, 1979    Non-patent document 4: Eur. J. Pharmacol., 510, pp. 167-180, 2005    Non-patent document 5: Kanzo (Liver, Journal of the Japan Society of Hepatology, 44, pp. 383-394, 2003    Non-patent document 6: N. Eng. J. Med., 334, pp. 1561-1567, 1996    Non-patent document 7: Biohem. Biophys. Res. Commun., 219, pp. 100-104, 1996    Non-patent document 8: J. Lipid Res., 45, pp. 1092-1103, 2004    Non-patent document 9: Kanzo, 26, pp. 605-612, 1985    Patent document 1: Japanese Patent Unexamined Publication (KOKAI) No. 8-67628    Patent document 2: Japanese Patent Unexamined Publication No. 5-229940    Patent document 3: Japanese Patent Unexamined Publication No. 2007-23002    Patent document 4: Japanese Patent Unexamined Publication No. 2007-45721    Patent document 5: Japanese Patent Unexamined Publication No. 2003-252792